Immunotherapy for tuberculosis: future prospects

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ImmunoTargets and Therapy

ImmunoTargets and Therapy 2016:5 37–45

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37

Immunotherapy for tuberculosis: future prospects

Getahun Abate

1

Daniel F Hoft

1,2

1_{Department of Internal Medicine,}

Division of Infectious Diseases, Allergy and Immunology, 2_Department

of Molecular Microbiology and Immunology, Saint Louis University, St. Louis, MO, USA

Correspondence: Getahun Abate Department of Internal Medicine, Division of Infectious Diseases, Allergy and Immunology, Saint Louis University, Doisy Research Center, 8th floor, 1100 S. Grand Blvd, St. Louis, MO 63104, USA Tel +1 314 977 5500

email [email protected] Daniel F Hoft

Department of Internal Medicine, Division of Infectious Diseases, Allergy and Immunology, Saint Louis University, Doisy Research Center, 8th floor, 1100 S. Grand Blvd, St. Louis, MO 63104, USA Tel +1 314 977 5500

Fax +1 314 771 3816 email [email protected]

Abstract: Tuberculosis (TB) is still a major global health problem. A third of the world’s population is infected with Mycobacterium tuberculosis. Only ∼10% of infected individuals develop TB but there are 9 million TB cases with 1.5 million deaths annually. The standard prophylactic treatment regimens for latent TB infection take 3–9 months, and new cases of TB require at least 6 months of treatment with multiple drugs. The management of latent TB infection and TB has become more challenging because of the spread of multidrug-resistant and extremely drug-resistant TB. Intensified efforts to find new TB drugs and immunotherapies are needed. Immunotherapies could modulate the immune system in patients with latent TB infection or active disease, enabling better control of M. tuberculosis replication. This review describes several types of potential immunotherapies with a focus on those which have been tested in humans.

Keywords: tuberculosis, HDT, immunotherapy, treatment

Introduction

Tuberculosis (TB) remains a major global public health problem. It is estimated that

a third of the world’s population is infected with Mycobacterium tuberculosis, the

causative agent of TB. There are

∼

9 million new cases of TB with 1.5 million deaths

annually.

1

_{Effective management of TB infection and TB disease requires treatment}

for at least 6 months. This long treatment duration, coupled with side effects of

anti-TB drugs, leads to noncompliance resulting in the emergence of drug-resistant anti-TB.

Of note, drug-resistant TB is more difficult to treat and significantly increases TB

control program costs in high TB endemic countries which have meager resources

to begin with.

2

The World Health Organization reports that several countries have increasing numbers

of patients with multidrug-resistant (MDR)-TB, TB caused by M. tuberculosis resistant to

at least isoniazid and rifampin.

1

_{To make the situation worse, only 20% of MDR-TB cases}

were started on appropriate drugs, with

,

50% successful treatment outcome.

1

Further-more, the number of MDR-TB cases increased three-fold between 2009 and 2013, mainly

due to lack of effective treatment.

1

_{In addition, several countries with high prevalence}

of MDR-TB also suffer from increasing numbers of cases of extensively drug-resistant

(XDR)-TB with resistance to isoniazid, rifampin, fluoroquinolones, and aminoglycosides.

The treatment of XDR-TB is even more difficult and the outcome unpredictable.

1,3

_Thus,

MDR- and XDR-TB are major global public health problems because of the lack of

effective treatment, the need for a much longer duration of treatment with second line

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Abate and Hoft

or experimental drugs, and the risk of further spread locally

and more widely through immigration. Enhanced efforts to

develop new TB therapeutics are urgently needed. The progress

in TB drug development has been slow and none of the new

drugs tested so far have allowed standard treatment regimen

shortening.

4

_{Host-directed therapy using immunomodulators}

is a promising approach which must be explored for better

control of TB. This paper reviews the strategies and prospects

for TB host-directed therapy immunotherapeutics.

TB latency, host immunity, and

M. tuberculosis

adaptation

A better understanding of the nature of host–pathogen

interac-tions is required for the development of immunotherapeutics

and to predict the roles of new immunotherapeutics for the

management of TB infection and/or disease. It is interesting

to note that only

∼

10% of M. tuberculosis-infected individuals

develop TB, but how the majority of infected people control

or clear the infection is not fully known. Until recently, it

was believed that latent TB infection (LTBI) is a state of

mycobacterial dormancy during which the immune system

contains virtually all persisting M. tuberculosis organisms in

a static state within granulomas.

5–8

_{An emerging consensus}

resulting in a paradigm shift in the field maintains that both

active TB and LTBI represent dynamic spectra with variable

levels of actively replicating and inactive bacilli in different

granulomas present in the same infected individual.

9,10

The immune response can greatly alter the proportions

and absolute numbers of actively replicating M. tuberculosis

in infected persons with concomitant changes in TB disease

risks. Because the infection is largely intracellular during

paucibacillary LTBI and early reactivation disease, T-cell

responses are critically important for protective immunity.

CD4

+

, Th1, and CD8

+

T-cell responses are involved in

the control of M. tuberculosis replication in vivo, as are

the cytokines they produce (eg, interferon [IFN-

γ

], tumor

necrosis factor [TNF]-

α

, and interlukin [IL]-2).

11–13

How-ever, these responses alone appear insufficient for bacterial

clearance as these T-cell subsets peak during active TB

dis-ease and decrdis-ease after spontaneous immunologic control

without eradication of TB infection. Other immune subsets

which tend to accumulate in mucosal tissues, including

γδ

T-cells,

14,15

_{CD1 restricted T-cells,}

16

_{and mucosa-associated}

invariant T-cells,

17,18

_{can impact on the levels of protective}

responses. Figure 1 summarizes protective and

counter-productive immune responses in TB.

M. tuberculosis has an incredible capacity to adapt

in vivo to a variety of stressful conditions. Pathogenic

M. tuberculosis can replicate intracellularly in professional

mononuclear phagocytes despite numerous mechanisms

available to kill intracellular bacilli. The pathogen switches

from predominant glucose metabolism when replicating at

high rates extracellularly to lipid-based metabolism after

uptake in phagosomes of mononuclear phagocytes. The

organism thrives in aerobic conditions reaching its highest

levels of replication, but can also survive prolonged periods of

microaerophilic and even anaerobic conditions. Certain gene

sets or regulons are activated intracellularly (eg, DosR) and

are thought to be involved in persistence of M. tuberculosis

during LTBI.

19

_{In addition, other genes associated with}

reactivation of LTBI have been identified (eg,

resuscitation-promoting factors).

20–22

_{Although previous data suggest that}

TB immunity is predominantly directed against antigens

pro-duced by replicating M. tuberculosis, there is a growing body

of evidence that latency-specific antigens are targeted as well.

M. tuberculosis mediates multiple immune evasion strategies,

including blockade of major histocompatibility complex

expression,

23–25

_{prevention of phagolysosomal fusion,}

26–28

_and

inhibition of IFN-

γ

signaling.

29–34

_{However, the majority of}

Potentially protective: CD4+ Th1

CD4+ Treg exhausted T-cells M∅: subtypes M2/AAM/

IL-10 PMN: predominant

type I IFN induced CD4+ Th17

CD8+ T-cells

MAIT cells Antibody responses γ9δ2 T-cells

Counterproductive responses:

Figure 1 Tuberculosis (TB)-specific mucosal immune responses are important

for protection against latent TB infection (LTBI) reactivation. Th1 CD4+ and Th17 CD4+ T-cells, CD8+ T-cells, γ9δ2 T-cells, mucosa-associated invariant T (MAIT) cells,

and sIgA/IgG antibody responses are potentially protective against LTBI reactivation which could reduce both TB disease and TB transmission.

Notes: All of these T-cell responses will be considered major targets for

immunotherapy in this project because they can recognize intracellular Mycobacterium tuberculosis, the major pathogen reservoir during LTBI. Mucosal antibody responses also could protect against initial infection and transmission, and are being studied in other funded work by our consortium of investigators. CD4+ regulatory T-cell, T-cell exhaustion, alternatively activated macrophages unable to kill intracellular

M. tuberculosis and type I IFN-induced polymorphonuclear (PMN) leukocytes can negatively regulate protective immunity in the lung.

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Dovepress Immunotherapy for tuberculosis

persons infected with TB never develop disease, indicating

that the host–pathogen balance can be tipped in favor of the

host leading to protective immunity.

Most primary and reactivation TB disease occurs in the

lung, and this is the main source of TB transmission. These

clinical facts combined with the accumulated knowledge in

this area indicate that an optimally effective immunotherapy

will need to target mucosal immunity in the lung.

TB immunotherapeutics

Immunotherapies ideally should modulate the immune

system in a way that helps the host control or eliminate

M. tuberculosis. Whole mycobacteria,

35,36

_{mycobacterial}

products,

37–39

_{cytokines, and drugs have been considered}

as possible immunomodulators. Table 1 summarizes

host-directed immunotherapeutics which have been tested for the

treatment of TB in humans.

M. vaccae

and other atypical mycobacteria

There are some controversies on the benefits of Mycobacterium

vaccae-based immunotherapy. A single injection enhanced

sputum culture conversion at 1 month and led to marked

radiographic improvement at 6 months,

40

_{but these promising}

findings were not reproducibly found in other studies.

41

None-theless, meta-analysis of 54 studies using intradermal injection

of M. vaccae reported that immunotherapy based on M. vaccae

could enhance sputum conversion and improve radiographic

changes.

36

_{Similarly, oral administration of M. vaccae enhanced}

sputum conversion in newly treated TB patients.

42

_Other

envi-ronmental mycobacteria, such as M. indicus pranii, also have

shown promising results in animal models.

43

RUTI

®

RUTI is a therapeutic vaccine made of detoxified cellular

fragments of M. tuberculosis, delivered in liposomes. It is

pre-pared by mechanically disrupting colonies of M. tuberculosis

in phosphate-buffered saline with 4% TritonX114, heating at

65°C for 40 minutes followed by lyophilization and

encapsu-lation in liposomes made of phosphatidyl choline.

44

_{In mice}

and guinea pigs, this therapeutic vaccine was found to have

potential for both prophylaxis and immunotherapy.

45

_{So far,}

it has been shown in Phase I and II clinical trials involving

healthy volunteers and cases with LTBI that this vaccine is

safe and immunogenic.

46,47

Table 1 Immunomodulating host-directed therapies for treatment of TB in humans

Therapeutics Composition No. of patients TB type (outcome) Refs

Mycobacterium vaccae

Killed, intradermal NA Meta-analysis of 54 studies on newly diagnosed pulmonary TB (improved sputum conversion and X-ray changes)

36

Capsule 41 (two arms)Φ _{Faster smear conversion} ₄₂

RUTI® _{Detoxified cellular fragments}

of Mycobacterium tuberculosis

NA Phase I and II clinical trials on LTBI cases or healthy volunteers (immunogenic, reasonable tolerability)

46,47

Autologous MSC MSC 30 MDR or XDR patients (21/30 with radiologic improvement) 54

v5 immunitor Inactivated pooled blood 55 (two arms) Re-treatment or proven MDR (higher rate of sputum conversion) 62 Cytokines and

cytokine inhibitor

IL-2 50 (two arms)¥

23 (three arms) 110 (two arms)¥

MDR-TB patients (better sputum conversion rate)

MDR-TB patients (decrease AFB smear counts with daily IL-2 compared to control or pulse IL-2)

New TB patients (significant delays in culture conversion)

73 71 72

IFN-γ 5

7 6

MDR-TB patients (all smear negative/improved) MDR-TB cases (no marked microbiologic effect) MDR-TB cases (no marked microbiologic effect)

67 68 69 etanercept 16§ _{HIv-positive TB cases (more rapid culture conversion compared}

to historical control)

76

Drugs/compounds High dose steroid 187 (two arms)§ _{HIv-positive TB cases (increased culture conversion at 1 month)} ₇₉

Levamisole 50§ _{Newly diagnosed pulmonary TB patients (improved radiology}

but no effect on smear conversion)

82 Albendazole 135 (two arms)§ _{New pulmonary TB patients (no effect on clinical, radiologic, and}

microbiologic outcome)

83

Thalidomide 15 (two arms)¥

30 (two arms)§

9/15 HIv-positive (clinical improvement) HIv-positive (no clinical difference)

102 103

Notes: Φ, different groups including drug-susceptible and drug-resistant cases; ¥, newly diagnosed pulmonary TB with drug-resistant or MDR-TB as exclusion criteria; §, newly diagnosed pulmonary TB and no drug susceptibility data reported. All TB cases were treated with multidrug-treatment regimen.

Abbreviations: AFB, acid-fast bacilli; HIV, human immunodeficiency virus; IFN, interferon; IL, interleukin; LTBI, latent TB infection; MDR, multidrug-resistant; MSC,

mesenchymal stem cells; NA, not applicable; XDR, extensively drug-resistant; TB, tuberculosis.

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Abate and Hoft

DNA vaccines

A number of DNA vaccines expressing relevant M.

tubercu-losis genes, Hsp65, ESAT-6, and Ag85A, have demonstrated

activity in M. tuberculosis-infected mice resulting in a one

to three log improvement in M. tuberculosis clearance.

48–51

More interestingly, an intramuscular DNA vaccine

contain-ing Hsp65 and IL-12 genes improved the survival of mice

infected with MDR-/XDR-TB.

52

_{This particular vaccine}

uses plasmid cDNA3.1 as a vector expressing Hsp65 and

IL-12 incorporated into virus-free envelopes derived from

the hemagglutinating virus of Japan. Furthermore, this same

DNA vaccine provided a 40% improvement in survival of

M. tuberculosis-infected primates.

52

_{These encouraging}

results suggest that some DNA vaccines may advance into

human clinical trials as adjuncts to chemotherapy.

Autologous MSC

Mesenchymal stem cells (MSC) are progenitor cells

constitut-ing a small proportion (0.01%) of the bone marrow.

53,54

_MSC

are present in various tissues and organs, including lungs,

55,56

and are involved in the repair of damaged tissues.

57,58

_These

cells have been tested for their potential to transform chronic

tissue inflammation into an environment capable of

induc-ing robust pathogen-specific immune responses. A recent

review describes the interaction of MSC with different cells

of the immune system.

59

_{Immunomodulatory functions of}

MSC are mediated by both cell-to-cell contact and release of

soluble mediators, such as tumor growth factor (TGF)-

β

and

prostaglandin E2.

59

_{A Phase I study with MSC given to 30}

MDR- or XDR-TB patients demonstrated that administration

of MSC within 4 weeks of initiation of anti-TB drugs was

safe and improved radiological changes.

54

v5 immunitor

V5 immunitor, derived from chemical- and heat-inactivated

pooled blood from hepatitis B and C virus-positive blood

donors, was originally developed for the management of

chronic hepatitis B and C.

60

_{The exact contents and how this}

product modulates the immune system remain to be

inves-tigated. It has been assumed that some of the blood donors

had LTBI and may have circulating M. tuberculosis antigens

which may stimulate immune responses.

61

_{It is also possible}

that circulating cytokines and/or chemokines in the pooled

blood, if they are not inactivated during chemical/heat

treat-ment, enhance T-cell responses to M. tuberculosis antigens

in TB patients. Alternatively, other unknown components

present could have adjuvant properties. In a Phase I clinical

trial, V5 immunitor oral therapy resulted in a markedly

better sputum smear conversion at 1 month after initiation

of treatment.

62,63

Cytokines and inhibitors

M. tuberculosis is an intracellular organism residing mainly

in monocytes/macrophages.

64

_{This makes cellular immune}

responses essential for inhibiting intracellular growth and

limiting dissemination. M. tuberculosis-specific T-cells

produce cytokines and effector molecules, such as perforin,

granzymes, and granulysin.

65,66

_{Thus, cytokines which}

enhance the expansion of T-cells and activation/ differentiation

of antigen presenting cells may help control infection. To this

effect, IL-2, IFN-

γ

, IL-12, and anti-TNF-

α

have been tried

in small numbers of clinical cases. Although it is difficult

to develop definitive conclusions from limited, and in most

cases nonrandomized trials, the adjunct use of cytokines

or anticytokines has shown some promise. Moreover, host

inflammatory response mediated by Th1 cytokines can

cause substantial morbidity; therefore, the doses and timing

of administration of cytokines may affect the outcome. The

adjunct use of IFN-

γ

and IL-12 in some cases of MDR-TB

resulted in favorable outcomes.

67–69

_{Adjunct aerosolized}

IFN-

γ

administered at a dose of 500

µ

g three times a week for

a total of 4 weeks to five MDR-TB patients was well tolerated

and led to smear conversion in all cases.

67

_{A similar study on}

six MDR-TB patients using aerosolized IFN-

γ

at a dose of

2 million units three times a week for 6 months showed that

all patients reverted back or remained culture positive at the

end of treatment.

69

_{This may also indicate that the response}

to IFN-

γ

may vary from patient to patient. In murine TB

models, IFN-

γ

administered with intranasal IgA resulted in

decreases in M. tuberculosis load in the lungs.

70

_{Despite some}

controversial results regarding the effects of IL-2 tested in

new TB cases,

71,72

_{intradermal injection of 500,000 IU of IL-2}

every other day at the first, third, fifth, and seventh months

of drug treatment of 25 MDR-TB patients led to a higher

rate of sputum conversion compared to controls receiving

only drug-treatment.

73

_{IL-2 also enhanced the activities of a}

pyrophosphate to enhance

γδ

T-cell responses and decrease

residual M. tuberculosis in the lungs of infected monkeys.

74

Anti-TNF-

α

antibodies which are commonly used for

treat-ment of severe rheumatological disorders increase the risk

of reactivation of TB.

75

_{However, in active TB, anti-TNF-}

α

may enhance culture conversion when combined with TB

multidrug therapy,

76

_{probably by delaying the formation of}

the so-called “persister” forms of tubercle bacilli, leading

to increased susceptibility to drug-mediated bactericidal

activity. Etanercept, an anti-TNF-

α

, administered at a dose

(5)

of 25 mg subcutaneously twice a week was tested on new

pulmonary TB cases who were human immunodeficiency

virus (HIV)-positive with a CD4 count

.

200/

µ

L. The

trial included age- and sex-matched controls and showed

that sputum culture conversion was slightly more rapid in

etanercept treated patients.

76

_{The role of etanercept}

admin-istered in the continuation phase of treatment to shorten the

duration of treatment may need to be studied. Similarly,

inhibitors of IL-4 and TGF-

β

were shown to enhance Th1

type immunity and help reduce M. tuberculosis bacterial load

in the lungs of infected mice.

77,78

Antibodies

M. tuberculosis infection induces both celI-mediated and

antibody responses. It has been shown that B-cell-deficiency

leads to higher bacterial burden and worse outcome following

M. tuberculosis infection.

79,80

_{Monoclonal antibodies against}

specific M. tuberculosis antigens have shown some

conflict-ing results.

81–83

_{This could be partly because of differences in}

types of antibodies and routes of administration. Using sera

from bacillus Calmette-Guerin (BCG)-vaccinated

individu-als, we had shown that antibodies enhance internalization

of mycobacteria by phagocytic cells.

84

_{Interestingly, these}

antibodies from vaccinated individuals significantly increased

the ability of macrophages to kill intracellular mycobacteria

and led to marked increase in M. tuberculosis-specific

cell-mediated immunity.

84

_{Further works to identify the}

combi-nations of monoclonal antibodies, routes, and frequency of

administration in animal models may be needed before M.

tuberculosis-specific antibodies are tested in clinical trials.

Drugs

Certain host-directed therapies focus on drugs as

immuno-modulators to facilitate M. tuberculosis clearance. Steroids,

levamisole, and vitamin D have been tried in humans. High

dose steroids have been tried in HIV-positive TB patients.

85

Although steroid-enhanced culture conversions at 1 month

have been observed, the side effects appeared to outweigh

the benefits. The antihelminthic drugs, levamisole and

albendazole, have been tested in combination with standard

anti-TB drugs in new cases of pulmonary TB. Helminth

infections induce Th2 predominant immune responses.

86

Moreover, helminth coinfection leads to Th2 and regulatory

T-cell dominant immune responses impairing TB-protective

Th1 responses.

86,87

_{Therefore, treatment of helminth}

infec-tions may modulate the immune response, inducing subsets

more able to limit the progression of disease. Unfortunately,

the results with antihelminthic drugs have not been very

encouraging so far. Levamisole given to new TB patients

resulted in improvements in radiological findings but no

change in smear conversion rate.

88

_{Recently, a randomized}

clinical trial with albendazole for 3 days in combination with

standard anti-TB drugs in patients with pulmonary TB and

helminth coinfection demonstrated no difference in clinical

score, smear conversion, and imaging changes compared to

placebo.

89

_{The roles of nutritional status, degree of}

immu-nosuppression from TB disease, and HIV coinfection on the

outcomes of the adjunct use of antihelminthic drugs need to

be studied further. The use of vitamin D for TB predates TB

chemotherapy. Vitamin D activates macrophages via toll-like

receptor signaling pathway leading to increased production

of mycobactericidal peptides, cathelicidin, and its active

form LL-37.

90

_{Unfortunately, clinical trials with vitamin D}

supplements have resulted in controversial results.

91

Other drugs targeting tyrosine kinases and phagosomal

acidification, autophagy, hydrolysis of cyclic adenosine

monophosphate and cyclic guanosine monophosphate,

inflammation, angiogenesis, and epidermal growth factor

receptor have shown encouraging results in murine TB

models. Imatinib is an inhibitor of Abelson tyrosine kinase

used mainly in the treatment of Philadelphia

chromosome-positive chronic myelogenous leukemia. Because Abelson

tyrosine kinase is important for the regulation of

lyso-somal pH in macrophages, inhibition of its function decreases

lysosomal pH and enhances the ability of macrophages to kill

M. tuberculosis.

92

_{Furthermore, the use of imatinib alone or}

in combination with rifampin has been found to decrease the

bacterial load in the lungs of M. tuberculosis-infected mice.

93

This drug appears to be generally safe although there are case

reports of interstitial lung disease associated with imatinib

and nilotinib, a second generation tyrosine kinase

inhibi-tor.

94,95

_{Metformin, an antidiabetic agent, is an autophagy}

inducer via activation of adenosine monophosphate-activated

protein kinase. Metformin inhibited the intracellular growth

of M. tuberculosis, restricted disease immunopathology,

and enhanced the efficacy of conventional anti-TB drugs

in mice.

96

_{Moreover, in a retrospective study of TB patients}

with diabetes mellitus, it was found that patients who were

on metformin had fewer pulmonary cavities and significantly

better survival.

96

_{Similarly, other autophagy inducers, such}

as statins (simvastatin, rosuvastatin) and gefitinib (an

inhibi-tor of epidermal growth facinhibi-tor recepinhibi-tor), were shown to

decrease bacterial load in M. tuberculosis-infected mice.

97,98

The safety and efficacy of imatinib, metformin, and statin

in murine TB studies make them potential candidates for

human clinical trials.

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Abate and Hoft

Treatment with the anti-inflammatory drug, ibuprofen,

resulted in decreases in the size and number of lung lesions,

decreases in bacillary load, and improvement in survival of

M. tuberculosis-infected C3HeB/FeJ mice.

99

_{Ibuprofen also}

enhances the anti-TB activities of the anti-TB drug,

pyrazi-namide, during the initial phase of treatment.

100

_Similarly,

other drugs which may reduce inflammation, prostaglandin

E2 and zileuton (a leukotriene inhibitor), decrease lung

colony forming units and improve survival in mice infected

with M. tuberculosis.

101

_{Phosphodiesterase inhibitors, such}

as sildenafil and cilostazole, likely by interfering with the

breakdown of cyclic adenosine monophosphate and cyclic

guanosine monophosphate and interfering with downstream

signaling events, shorten the duration of TB treatment in

mice.

102

_{CC-3052, a new phosphodiesterase-4 inhibitor and}

thalidomide analogue, decreased lung pathology and bacterial

load significantly when combined with isoniazid in a rabbit

TB model.

103

Knowledge gaps and novel strategies

Most of the studies on immunotherapy so far have focused on

TB treatment. This may help shorten standard treatments or

improve the management of MDR/XDR-TB. Because a third

of the population is infected with M. tuberculosis,

immuno-therapeutics which enhance the eradication of latent infection

could have a major impact on TB control. The effects of new

immunotherapeutics/vaccines on the progression or

reactiva-tion of LTBI in humans remain to be studied.

Because most cases of TB are pulmonary,

immunothera-peutics may give a better outcome if they modulate mucosal

immune responses. Lessons from TB vaccine studies should

be applied to new immunotherapeutics. Numerous animal

and human studies demonstrate that in general, mucosal

vaccinations induce more effective mucosal immunity than

systemic vaccinations. With regard to TB mucosal

immu-nity, murine studies with BCG and new TB vaccines clearly

demonstrated that mucosal vaccination via the intranasal

route induced superior protection against subsequent aerosol

challenges with M. tuberculosis.

104–106

_{It was further shown}

that mucosal T-cells present in the lung airways of mice

post-vaccination were the best predictors of protective immunity,

and when transferred intratracheally these cells alone could

protect against M. tuberculosis aerosolized challenges.

105,107

Therefore, approaches which facilitate the recruitment of

relevant M. tuberculosis-specific T-cells to the lung and limit

nonspecific inflammation should be studied. Host-directed

therapy potentially could provide exciting new avenues for

the management of LTBI and TB disease, providing hope

of shortening standard LTBI and TB treatments as well as

improving treatment of MDR/XDR-TB.

Disclosure

The authors report no conflicts of interest in this work.

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